Cerebral autoregulation that maintains perfusion in response to fluctuations of systemic blood pressure (BP) is lost post-stroke and traumatic brain injury (TBI). Noninvasive bedside methods are urgently needed to identify people with impaired autoregulation who may be at increased risk for stroke and adverse outcomes. The phase I goals are: 1) To develop and optimize the multimodal pressure flow (MMPF) method, a new approach to quantify cerebral autoregulation from nonstationary blood pressure (BP) and cerebral blood flow velocity (BFV) fluctuations using transcranial Doppler ultrasound. The major breakthrough is that the MMPF now allows measurement of instantaneous BP and BFV phase relationships over longer time period from spontaneous fluctuations under resting conditions. We will apply the MMPF method to the assessment of dynamic autoregulation using the instantaneous BP-BFV phase relationships during supine resting condition, and during the Valsalva maneuver and the sit-to-stand test. The MMPF analysis decomposes complex BP and BFV signals into empirical modes, representing their instantaneous frequency-amplitude modulation. Instantaneous BP-BFV phase relationships will be used as a measure of dynamical autoregulation. 2) To validate autoregulation measurements derived from the MMPF using BP-BFV responses to these physiological maneuvers, and to compare them to standard autoregulation indices obtained in populations of 118 healthy, 75 hypertensive, 30 diabetic and 50 stroke subjects. 3) To validate MMPF measurements using invasive measurements of intraarterial pressure (ABP), intracranial (ICP) and cerebral perfusion pressure (CPP=ABP-ICP) and BFV in 30 patients with traumatic brain injury, using existing databases from the Syncope and Falls laboratory (SAFE) at the Beth Israel Deaconess Medical Center and from the University of Cambridge. The assessment of cerebral autoregulation is of vital importance in many areas of clinical and investigative medicine. Therefore, in Phase II we plan to incorporate the MMPF software into existing transcranial Doppler systems in order to provide a new, widely applicable, practical tool for evaluation of cerebral autoregulation in clinical settings. The analysis technique developed by this project may help early detection of subjects at high risk of stroke. The quantitative measurements derived from this innovative technology can also serve as indices for monitoring post-stroke patients. Therefore, this project may have substantial socioeconomic impact. [unreadable] [unreadable] [unreadable]